Nitrosamines and nitrosamides having a variety of molecular structures, are often toxic to animals and humans. Most nitrosamines and nitrosamides have also been shown to be carcinogenic and usually mutagenic as well.
Under conditions of pH and temperature similar to those found in mammalian stomachs, nitrites react with secondary and tertiary amines to produce nitrosamines. This is potentially detrimental for humans since many foods, particularly cured meats, have sodium nitrite added and many commonly used foods and drugs contain secondary and tertiary amines. Typical of drugs which have such amines are piperazine, phenmetrazine, aminopyrine, primaquine, pemaquine, physostigmine, synephrine, sulfanilylurea, neohydrin, oxytetracycline and the like.
Foods can contain such naturally occurring amines as dimethylamine, diethylamine, trimethylamine, pyrrolidone, piperidine, proline, hydroxyproline, arginine, 2-dimethylaminoethyl acetate, 2-dimethylaminoethanol, methyl ester of N,N-diethylglycine, N,N-dimethylglycine and the like.
Similar nitrosation reactions can occur with amides, particularly secondary amides, to form N-nitrosamides, most of which have been shown to be carcinogenic or mutagenic or both.
Nitrites can also be formed by in vivo reduction of nitrates. Nitrates and nitrites in combination with secondary and tertiary amines are, thus, considered potential precursors in the formation of nitrosamines and nitrosamides. Nitrates are natural constituents of plants and occur in large amounts in many vegetables. Some water supplies also have high nitrate content.
Nitrite is also formed in the human mouth by the action of oral bacteria in reducing nitrate to nitrite. This production of salivary nitrite can persist for many hours due to the recycling of dietary nitrate into the saliva. Nitrite can also be formed from nitrate in vivo in the stomach itself by the action of bacterial flora, when the pH of the stomach rises for a prolonged period of time. This pH rise in the stomach, or achlorhydria, may be the result of disease (i.e., pernicious anemia, chronic atropic gastritis, etc.) or induced by drugs (e.g. cimetidine). Thus, a substantial amount of nitrite can pass into the stomach over a 24 hour period.
N-nitroso compounds (nitrosamines and nitrosamides) are a unique group which includes very highly potent carcinogenic agents. Once formed and present in vivo, these N-nitroso compounds are not easily or readily converted back to their precursors. Instead, they metabolize in vivo to, or are otherwise converted to, alkylating agents which are the terminal or proximal carcinogens. Control of the N-nitroso carcinogenic compounds has, to date, depended on the use of blocking agents that prevent their formation, i.e. by, preferentially, reacting with the nitrosating agent. As discussed above, nitrites in the stomach, from, e.g. food additive use, from microbiological or enzymatic conversion of nitrate in saliva or the stomach itself, are a source of nitrosation for susceptible amines or amides to produce, in the stomach, the N-nitroso carcinogenic compounds.
This invention is directed to a means of preventing the in vivo formation of nitrosamines and nitrosamides in the stomach resulting from the concurrent presence, by administration or ingestion, of nitrites and amines. To be so effective, however, the preventive formulations must be retained in the stomach with the active ingredient, a N-nitroso compound blocking agent, slowly released over an extended period of time in the stomach itself.
In most controlled release preparations known to the pharmaceutical art, the active ingredients are either coated with varying thicknesses of some type of relatively insoluble material or are imbedded into a rigid lattice of resinous material. In such preparations, the object is to continuously provide drug for absorption into the blood stream to replace the amount eliminated while the dosage form is passing through the gastrointestinal tract of the patient.
Such conventional formulations, which are not specifically retained in the stomach and which release medicament in the intestines or during passage in most of the gastrointestinal tract, are not suitable for use in the method of this invention wherein the active ingredient must be retained specifically in the stomach for continuous release over long periods in the stomach itself.
In the controlled release formulations used in the practice of this invention, formulations contained in capsules or tablets remain buoyant and freely floating in the gastric fluid for an extended period of time during which substantially all of the active ingredient contained in the formulations is released in the gastric fluid.
Formulations, either capsules or tablets, which remain intact and buoyant in the gastric fluid while substantially all of the medicament is released therefrom are described in the art. See, for example, U.S. Pat. Nos. 4,126,672; 4,140,755 and 4,167,558 where formulations for the preparation of controlled release capsules or tablets for oral administration are described.
The capsules are hydrodynamically balanced to have a bulk density (specific gravity) of less than one when in contact with gastric fluid and, therefore, will remain floating in gastric fluid which has a specific gravity of between 1.004 and 1.010. These controlled release capsule formulations comprise a homogeneous mixture of one or more medicaments with one or more hydrophilic hydrocolloids. Upon dissolution of the gelatinous capsule and contact of the formulation with the gastric fluid, the capsule will form on its surface a soft gelatinous mass, maintaining the shape of the capsule. The medicament is slowly released from the surface of the gelatinous mass which, due to its density, remains buoyant in the gastric fluid. Ultimately, after substantially all of the medicaments therein are released, the gelatinous mass disperses.
Hydrodynamically balanced tablets can be made on conventional tableting equipment. It is critical that the tablets are compressed to a degree of hardness such that they will acquire a bulk density of less than one in contact with gastric fluids. However, tablets which initially have a density greater than one will be buoyant in gastric fluids. This buoyancy results from a combination of an increase in the bulk volume of the tablet when it contacts gastric fluids due to the hydration and swelling of the hydrocolloid particles on the tablet surface and the internal voids in the tablet center remaining dry due to the barrier formed by the hydrocolloid particles. Therefore, it is critical that the tablets are not compressed to a degree of hardness such that the porosity is materially reduced and the hydrocolloid particles on the tablet surface are compacted so tightly that rapid hydration is retarded. It will be appreciated that the maximum hardness to which a tablet having an initial density greater than one can be compressed will vary both with the initial density of the formulation and the size of the tablet. The hardness for any tablet will be between the maximum at which a buoyant tablet can be produced in accordance with the teachings herein and a minimum required for tablets to meet basic pharmaceutical tests of stability during shipping and the like. This range of hardness can be easily determined by standard pharmaceutical hardness measurements combined with testing of the buoyancy of samples of tablets of different hardness in gastric fluid. Such determinations are considered to be within the purview of the skilled artisan.
The hydrated barrier layer of the outermost hydrophilic colloid slowly dissolves releasing medicament. There is also a release of medicament by leaching action at or near the surface of the mass. As new surface is exposed to gastric fluid it becomes hydrated, thus maintaining the integrity of the barrier. This process is continuously repeated until the medicament is substantially leached out. Thereafter the remaining matrix which is still buoyant in gastric fluid slowly disperses and is eliminated. It has been found that the release pattern and resulting blood levels attained with these hydrodynamically balanced controlled release formulations have advantages over other controlled release mechanisms.
To prevent the formation of N-nitroso carcinogenic compounds in the stomach, block agents are used. These blocking agents act primarily either in the aqueous phase or in the lipid phase of the gastric fluid. Aqueous phase N-nitroso compound blocking agents include sulfite, bisulfite, cysteine, certain phenols such as gallic acid, tannic acid and the like, ascorbic acid (vitamin C) and its salts, erythorbic acid and its salts, ferulic acid and its salts, caffeic acid and its salts and the like. Lipid phase N-nitroso compound blocking agents include the free tocopherols, particularly alphatocopherol (vitamin E), propyl gallate, ascorbyl palmitate, ascorbic acetals of C-8 to C-16 aldehydes, ethoxyquin, tertiary butyl hydroxyquinone, nor-dihydroguariaretic acid (NDGA), 8-hydroxyquinoline and the like.
The use of such materials as blocking agents in preventing N-nitroso compound formation is well known in the art. Detailed summaries of such use are found in: Newmark, H. L. and Mergens, W. J., Applications of Ascorbic Acid and Tocopherol as Inhibitors of Nitrosamine Formation and Oxidation in Foods; In Criteria of Food Acceptance, ed. by J. Solms and R. L. Hall, Switzerland, Forster Verlag AG/Forster Publishing Co., 1951; Alpha-Tocopheral (Vitamin E) and Its Relationship to Tumor Induction and Development ed. by M. Zedech and M. Lipkin, New York, Plenum Press, 1981 (in press) and Douglas, M. L. et al. The Chemistry of Nitrosamine Formation, Inhibition and Destruction, in J. Soc. Cosmet. Chem. 28:p 581, 1978.
Among the medicaments listed in U.S. Pat. Nos. 4,126,672, 4,140,755 and 4,167,558 as possible active ingredients amenable to use in controlled release formulations are the vitamins used as nutritional supplements. There is, however, no disclosure of formulations containing combinations, as aqueous phase and lipid phase N-nitroso compound blocking agents, of the specific vitamins C and E used as safe chemical agents for the prevention of the formation of N-nitroso compounds in the stomach nor is there any disclosure of the quantity or ratio of these vitamins in the formulations.